It has been proposed that endogenous cannabinoids contribute to the valuation of various reinforcers including brain stimulation reward (BSR), highly palatable food and abused drugs such as cocaine, in part by modulating neurotransmitter levels including dopamine (Gardner, 2005). This proposal will investigate the neurobiological mechanisms that accompany the well-documented anti-relapse effects of cannabinoid receptor (CB1) antagonists (Fattore et al., 2007). Our prior studies showed that coincident changes in firing and subsecond dopamine release occur at cues signaling reward availability during BSR and are functionally linked via D1 receptor activation (Cheer et al., 2007a). We have also shown that increases in subsecond dopamine elicited by drugs of abuse of different classes (qualitatively similar to those observed in BSR and food seeking) are uniformly inhibited by administration of the cannabinoid CB1 receptor antagonist rimonabant. Given these findings, we propose four experiments to examine the mechanisms through which rimonabant may potentiate extinction learning to enhance extinction and prevent relapse. The first experiment will evaluate reinforcement- specific cell firing and subsecond dopamine release in the shell of the nucleus accumbens (NAc) during cue- induced reinstatement to BSR following CB1 receptor blockade at specific times during extinction learning, to examine if endogenous cannabinoid-mediated effects on acquisition or consolidation negatively affect retrieval of the extinction response. An identical protocol will be utilized in experiment 2 for reinstatement of high palatability food seeking (Ward et al., 2007). This will clarify if cue-encoding is similar between BSR and food seeking and whether its extinction and retrieval requires common CB1 receptor-mediated mechanisms. Experiments 3 and 4 will determine whether attenuated accumbal subsecond dopamine release, single-unit and ensemble encoding accompanies CB1 receptor antagonist-mediated enhancement of extinction retrieval during cue-evoked reinstatement of cocaine seeking (De Vries et al., 2001), following abstinence periods that produce an "incubation of craving" effect (Grimm et al., 2001). Considering recent clinical evidence of rimonabant-induced enhanced cessation of the use of tobacco and its potential beneficial effects on relapse to other drugs of abuse and on food intake (obesity), a clearer understanding of the neurobiological role of endogenous cannabinoids on relapse to abused drugs, as well as to natural rewards, is paramount with respect to the development of new treatments for these diseases. Therefore, through the examination of interactions between dopaminergic and endogenous cannabinoid signaling during extinction learning, the present proposal will likely lead to new insights on the pathogenesis of drug addiction and relapse. PUBLIC HEALTH RELEVANCE: One of the major problems in the treatment of drug abuse is the renewal of drug craving and seeking upon environmental triggers, commonly known as relapse, after protracted abstinence periods. Clinical experience has reported the availability of very few proven effective approaches for use in crisis intervention, detoxification, stabilization and harm reduction in addicted patients. By employing new pharmacological tools with promising therapeutic value in a broad spectrum of addictive substances, a better understanding of the neurobiological mechanisms triggering relapse in the treatment of drug addiction and dependence will be gained.